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Thyroid Function Test Learning objectives

Normal functioning of gland including production and regulation of thyroid . Various parameters used to assess thyroid function.  in various thyroid dysfunctions. Analytical and radiological methodologies to assess thyroid functions. A brief review of Thyroid gland

•Butterfly shaped gland located in front of neck.

• Weight : 15 – 20 gm

• Thyroid follicle is the secretory unit

• two-in-one gland : oThyroid follicular cells secrete thyroid

o Parafollicular (C) cells secrete THYROID SYNTHESIS AND TRANSPORT

Products of Thyroid gland • Mono-iodotyrosine ( MIT) and Di-iodotyrosine ( DIT)

• – Thyroxine (T4) ( 3,5,3’,5’-L-tetraiodothyronine) – Tri-iodothyronine (T3) ( 3,5,3’-L- )

3,3’5’-L-triiodotyrosine • Reverse T3 (rT3 ) ( ) Peripheral of thyroid hormones

• Only T3 binds intranuclear thyroid hormone receptors (TRs)

• De-iodinases remove moiety from T4

• 3 types D1, D2 and D3

• 40 % T4  T3 by D1 and D2 • 45 % T4  rT3 by D1 and D3 Biological functions of thyroid hormone 1. Growth and development of fetus and child

2. Calorigenic effect or is the major effect of thyroid hormone. – It is mediated by uncoupling of oxidative phosphorylation.

– Increases O2 consumption within tissue – Enhances mitochondrial metabolism – Increases sensitivity to 3. Earliest effect of T4 is stimulation of RNA synthesis and consequent increase in synthesis. Higher concentration of T3 causes protein catabolism and negative nitrogen balance.

4. (BMR) is increased(Thyroxine increases cellular metabolism)

5. and oxidation are increased.

6. is increased. Cholesterol degradation is increased and hence cholesterol level in is decreased, which is another hallmark of . Regulation of thyroid hormone production Thyroid hormones in circulation

• Both T3 and T4 are highly plasma protein bound. • Unbound form is biologically active. Binding

• Main function maintainance of a large pool of hormone that can be mobilised when needed .

• Plasma proteins that bind thyroid hormones are – Albumin – more CAPACITY – Prealbumin – (thyroxine binding prealbumin ) – Globulin – thyroxine binding globulin (TBG) – more AFFINITY • T3 & T4 are LIPOPHILLIC ; their free forms in plasma are in equillibrium with a larger pool of protein bound thyroid hormones

• Free thyroid hormones are added to the circulating pool by the thyroid

• These free hormones are the physiologically active forms that send feedback to inhibit pitutary of TSH Alteration in Thyroid hormone binding proteins

Increase in TBG concentration Decrease in TBG concentration or affinity or affinity Genetic causes Genetic causes Non thyroidal illness such as Non thyroidal illness such as HIV infections , hepatitis an surgical stress, chronic disease, producing tumors nephrotic syndrome Pregnancy , new born such as anabolic , large Drugs such as OCPs, , doses of Tamoxifen Clinical disorders of Thyroid gland • Based on history, clinical examination and laboratory results; patients can be classified into : » Euthyroid » Hypothyroid » Hyperthyroid Hyperthyroidism Mental dullnes Nervousness Increased sleep, lethargy Sleeplessness Hoarseness of voice Excessive sweating Cold intolerence Heat intolerence Weight gain Weight loss Constipation Diarrhoea Signs : Bradycardia, dry skin Signs : tachycardia , systolic murmurs Etiology of Primary and Secondary Hypo & Hyperthyroidism Hypothyroidism Hyperthyroidism

ENDOGENOUS ENDOGENOUS

Autoimmune thyroid diseases : Autoimmune thyroid diseases :  Hashimoto thyroiditis  Graves Atrophic thyroiditis   Post partum thyroiditis  Post partum thyroiditis

Na+ / pump dysfunction Toxic multinodular goiter : Toxic adenoma, familial Thyroperoxidase deficiency, HCG secreating tumors. Developmental disorders etc. EXOGENOUS EXOGENOUS

Iodine excess or deficiency , dietary Thyroid destruction by viral or bacterial goiterogens thyroiditis Drugs such as , thionamides Iodine induced hyperthyroidism Thyroid auto antibodies

• Main auto antibodies are : • autoantibodies ( TPOAs) • autoantibodies ( TGAs) • Thyroid microsomal autoantibodies ( TMAs) • Thyroid autoantibodies ( TRAs) Detection of thyroid antibodies

Antibody Name Disease Thyroglobulin autoantibodies ( TGAs) Thyroid peroxidase autoantibodies ( Hashimoto s Thyroiditis (auto immune) TPOAs)

Thyroid stimulating immunoglobins Graves disease Indications for Thyroid function tests :- 1. Evaluation of thyroid gland in case of clinical suspicion of thyroid disorder – Hyperthyroid – Hypothyroid • Primary (TSH High ) • Secondary or tertiary (TSH low) 2. Follow up 3. Screening of congenital hypothyroidism.

??? Screening of asymptomatic individuals TSH

Normal Elevated Decreased

No further testing FT4 FT4 Sub clinical T3 hypothyroidism

T3 toxicosis Elevated Decreased Elevated Decreased Primary Primary Central hyperthyroidism hypothyroidism hyperthyroidism

If hyperthyroid : TSH If Euthyroid : dependent Thyroid hormone hyperthyroidism resistance Analytical Methods Routine TFT Parameters

TSH Thyroid stimulating 0.5 – 5 mIU/L hormone

T4 Serum Total thyroxine 65 – 150 nmol/L

T3 Serum total 1.8 – 3 nmol / L triiodothyronine fT4 Free T4 10 – 23 pmol / L

fT3 Free T 3 4 – 7.4 pmol / L

Thyroid Autoantibodies TPOAs (Thyroid Peroxidase Antibodies),TGAs (Thyroglobulin Antibodies) , TMAs(Thyroid Microsomal Antigen) TSH • Best initial test for screening • Hypothyrodism elevated TSH ( > 5 mIU/L) • Hyperthyroidim low TSH ( < 0.5 mIU/L) • All modern TSH methods based on ELISA TSH

• Specimen collection and storage – Serum or plasma is used – Stable for 5 days at 2-8 oC and 1 month when frozen • Secretion is circadian , peak between 2 am and 4 am and nadir between 5 pm to 6 pm • TSH surges immediately after birth ( 25 –160 mIU/L) and stablizes in first few weeks. • Decrease in first trimester due to HCG stimulation Measurement of Total thyroxine ( T4 )

• Principal hormone secreted by thyroid gland • Highly protein bound ( > 99.9 %)

• Total T4 gives very limited clinical information

• If normal serum binding capacity: total T4 is inversely proportional to TSH and proportional

to free T4 Measurement of Total triidothyronine

( T3 ) • Principal active thyroid hormone. • Only 99 % is bound but binding is weak

• Useful in diagnosis and monitoring of T3 thyrotoxicosis Other Thyroid parameters

• Thyroglobulin ( Tg) • Thyroid binding globulin ( TBG)

• Reverse T3 ( rT3 ) • Tg mRNA in serum • Thyroid autoantibodies Cholesterol

• Hypothyroidism : cholesterol level ↑ ( cholestrol carrying lipoprotein degradation decreased • But not diagnostic as raised in other conditions like  DM , HTN , obstructive jaundice • However this level effective in monitoring the effectiveness of therapy Radioactive iodine uptake

• Administration of radioactive iodine / technitium allows visualisation of thyroid tissue in neck and throughout body • It helps to reveal whether uptake is low or high . Esp in following diseases • Hemithyroid (toxic hyperactive nodule) • Cold nodule ( nodule fails to take tracer ) • Ectopic thyroid tissue TRH(Thyrotropin Releasing Hormone) Response Test

• Determining basal levels and levels 15 – 30 mins after an IV bolus of TRH

• TRH administration will stimulate the production of TSH

• If the Hypothalamo – Pitutary – Thyroid Axis is

normal ; T3 , T4 will be increased : • An abnormal response is seen in: • Hyperthyroidism : the effect of high T4 overpowers the effect of TRH . Here thyroid hormones are elevated • Hypopitutarism : the pitutary could not respond to TRH . Plasma Thyroid levels  subnormal • Primary Hypothyroidism : exaggerated response , negative feedback effect of T4 reduced Lab findings in Hyperthyroidism

Plasma fT4 Plasma Response total T3 TSH to TRH and T4 Grave’s Increase High Decrease Nil Disease Increase Toxic Increase High Decrease Nil Goiter Increase T3 T3 Increase Decrease Sluggish Toxicosis Increase T4 Normal Excess Increase Mild Decrease Sluggish intake of Increase thyroxin Lab Findings in Hypothyroidism

T3 and T4 in blood TSH in blood Response to TRH Primary Decreased Increased Exaggerated Hypothyroidism Response Secondary Decreased Decreased No Response Hypothyroidism Condition Conc . Total Free Plasma Plasma TSH Clinical State

Of Plasma T3 T4 T3 T4 Binding Protein

Hyperthyroidism Normal High High Low Hyperthyroid

Hypothyroidism Normal Low Low High Hypothyroid

Estrogen , High High Normal Normal Euthyroid Methadone , major tranquilizers Glucocorticoids , Low Low Normal Normal Euthyroid androgens , danazol Assignment

I. Describe synthesis and secretion of thyroxine. II. Enumerate the thyroid function tests. Describe any one of them in detail. III. Which parameter is seen in congenital hypothyroidism a) Increased TRH b) Decreased TRH c) Increased TSH d) Decreased TSH

IV. Which condition is associated with increased T3 a) Primary hyperthyroidism b) Primary hypothyroidism c) Primary hypoparathyroidism d) Primary hyperparathyroidism V. Thyroxine formation requires which trace element a) Fluoride b) Calcium c) Iodide d) Phosphorus Viva questions

1. What is the precursor of thyroxin?

2. What is the ratio of T3 and T4 in blood? 3. What is the function of TSH? 4. What is the function of thyroid hormones 5. Deficiency of thyroxine results in ? 6. What are the salient feature of hypothyroidism? 7. What is the cause of Graves Disease?